7 Tesla and Beyond

Abstract

Ultrahigh magnetic fields offer significantly higher signal-to-noise ratio, and several magnetic resonance applications additionally benefit from a higher contrast-to-noise ratio, with static magnetic field strengths of B₀ ≥ 7 T currently being referred to as ultrahigh fields (UHFs). The advantages of UHF can be used to resolve structures more precisely or to visualize physiological/pathophysiological effects that would be difficult or even impossible to detect at lower field strengths. However, with these advantages also come challenges, such as inhomogeneities applying standard radiofrequency excitation techniques, higher energy deposition in the human body, and enhanced B₀ field inhomogeneities. The advantages but also the challenges of UHF as well as promising advanced methodological developments and clinical applications that particularly benefit from UHF are discussed in this review article.

Currently, clinical magnetic resonance (MR) examinations are mainly performed at static magnetic fields of 1.5 and 3 T. However, since the later 1990s, also many studies in humans have been performed at magnetic fields higher than 3 T.^1–7 In the period around the turn of the millennium, the first 2 ultrahigh field (UHF) MR systems for human MR applications were installed and applied in vivo,^1,5 with static magnetic field strengths of B₀ ≥ 7 T currently being referred to as UHF. Based on the research work performed by these and subsequent research UHF systems, the first regulatory approval of a commercial 7 T MR system for clinical neuro and musculoskeletal (MSK) imaging as a medical device occurred in 2017.⁸ In the meantime, a second manufacturer has also followed with the clearance of a 7 T MR scanner as a medical device. Until the first approval as a medical device, more than 70 UHF MR systems including several 9.4 T MR scanners were in operation as research devices. After approval, the number of UHF MR devices has increased noticeably, with a total number of UHF systems of approximately 100. The approval makes it possible not only to conduct basic research with these scanners, but also to perform clinical diagnosis. This simplifies studies including larger cohorts, because they can be carried out, for example, as part of clinical measurements with prior consent of the patient. In addition to the aforementioned MR systems with 7, 8, and 9.4 T, a first 10.5 T whole-body MR scanner is in operation,⁹ and 11.7 T magnets for human MR imaging (MRI) are in the process of being launched at NeuroSpin CEA in Paris,¹⁰ at the National Institutes of Health in Bethesda, and at the Gachon Medical University in Incheon. These systems are expected to provide very promising opportunities in future MR research.

In this review article, we discuss various promising MR methods and applications at B₀ ≥ 7 T. Because of the large number of studies performed at UHF, we cannot guarantee completeness. The length of the individual text sections does not necessarily reflect the frequency of use or the readiness of the method for clinical application. Furthermore, the majority of the studies cited were not performed with product sequences and/or hardware but with custom-built hardware and/or sequences. Some of these techniques are therefore not directly available for immediate clinical use.

PHYSICAL CHALLENGES AND ADVANTAGES OF ULTRAHIGH FIELD

In human MR applications, the measurement noise is sample-dominated in most cases, and for this case and for resonance frequencies at least up to approximately 64 MHz (¹H frequency at 1.5 T), a linear increase in signal-to-noise ratio (SNR) can be expected.¹¹ However, at UHF strengths (B₀ ≥ 7 T) and thus higher proton resonance frequencies, even a higher increase in SNR has been observed for ¹H MR applications in some cases, for example, an SNR increase proportional to B₀ raised to the power of 1.65 to 2.1.^9,12,13

Thus, MRI at UHF provides a significant increase in the MR signal compared with 1.5 and 3 T, which are currently the standard field strengths in clinical MRI. This signal gain with increasing B₀ can be used on the one hand to achieve a higher spatial resolution in the same measurement time (see sections High-Resolution Morphological Magnetic Resonance Imaging and X-Nuclei Magnetic Resonance Spectroscopy and Magnetic Resonance Imaging) or to achieve similar image quality in a shorter measurement time, which also allows for a higher temporal resolution in dynamic MRI techniques.

In addition to SNR, the contrast-to-noise ratio (CNR) plays an important role in MRI techniques. Contrast generation in MRI is generally based on the interactions between nuclear spins and their variable environment, and there is a variety of contrasts that depend on diverse parameters (eg, T₁, T₂, …) that change differently with increasing B₀. For example, the longitudinal relaxation times T₁ of protons lengthen with B₀. As a result, time-of-flight (TOF) MR angiography and arterial spin labeling benefit from increased background suppression.^14–17 However, for applications that require, for example, full relaxation before the next excitation, longer T₁ times result in longer measurement times at higher fields.

Furthermore, higher magnetic fields provide increased susceptibility sensitivity,^17–19 which is of great advantage for susceptibility-weighted imaging (SWI) and quantitative susceptibility mapping (QSM) (see section High-Resolution Morphological Magnetic Resonance Imaging) but also for functional MRI (fMRI) (see section Functional Magnetic Resonance Imaging for Mapping Neuronal Activity). In other applications, however, this fact can lead to increased susceptibility artifacts including geometric distortions and signal dropouts in the images.

For diffusion-weighted imaging (DWI), higher SNR at UHF also offers the possibility of increased resolution and/or high b-value acquisition.²⁰ However, increased B₀ and radiofrequency (RF) transmit field inhomogeneity, shorter T₂ relaxation, and higher specific absorption rate (SAR) levels are challenges that need to be addressed at UHF.²⁰ Despite short T₂, SNR gain at UHF has been demonstrated to be feasible with short echo times,²¹ for example, by combining parallel imaging and partial Fourier acquisition.^22,23 Further echo time reduction can be achieved by reducing the field of view²⁴ and readout-segmented echo planar imaging.²⁵ Dielectric pads have been suggested for addressing RF transmit field inhomogeneity.²³ Such technical advances have paved the way for human applications of DWI at UHF.

In spectroscopic applications, a higher magnetic field strength leads to larger splitting of the resonance frequencies in the MR spectrum, which can be beneficial, for example, in ¹H MR spectroscopy (MRS; see section Proton Magnetic Resonance Spectroscopy and subsection Phosphorus-31 Magnetic Resonance Spectroscopy) or chemical exchange saturation transfer (CEST; see section Chemical Exchange-Sensitive Magnetic Resonance Imaging) acquisition techniques.^26–28

Radiofrequency Characteristics of ¹H at Ultrahigh Field: Issues With Field Inhomogeneity

With increasing field strength and thus increasing resonance frequency, the wavelength for ¹H RF excitation in humans approaches the size of the head, body part, or body, causing standing wave effects. For ¹H MR applications at approximately 300 MHz or higher for B₀ = 7 T and beyond, strong inhomogeneities in the transmit field (B₁⁺) and in the receive field (B₁⁻) can occur, which can lead to cancellations in the MR images, impaired contrasts, and regional peaks in the SAR distribution.^17,29

Thus, coil designs that are used at lower B₀, such as standard surface and birdcage coils, can therefore exhibit disadvantageous behavior at UHF for the excitation of medium to large excitation volumes.^4,30 In body MR applications, birdcage coils are practically not applicable because of the enormous inhomogeneities in B₁⁺ and B₁⁻. Therefore, the manufacturers of MR systems do not offer an integrated body coil behind the bore liner of the magnet, and also so far no other ¹H RF body coil for MRI of the human torso. Dedicated coils for excitation (transmission) and detection (reception of the spin signal) are therefore required for each specific body region.

To deal with the challenges of inhomogeneous RF fields and enable ¹H MRI, even in larger body regions, excitation hardware and techniques have been further developed during the last decades, using multiple transmit RF coil elements and multiple transmit channels. With so-called B₁⁺ shimming or static RF shimming, a transmit coil array is driven with a single RF waveform, and the phases in the coil elements are independently adjusted. This technique was a first step to improve the B₁⁺ field homogeneity, and it achieves homogeneous excitation in small regions of interest (ROIs) such as the prostate or a specific brain region. In larger ROIs, the time-interleaved acquisition of modes method is a valuable extension³¹: 2 (or more) measurements with identical parameters but with different B₁⁺ shim weights are acquired. The acquired data are merged, and a single image is reconstructed with reduced contrast variations.

With dynamically applied B₁⁺ shimming, it is possible to switch to another shim after an RF pulse.³² This allows RF pulses with different static shims to be played out, which can be used if the pulses are to excite different ROIs, for example, for saturation, inversion, and so on.

Dynamic or full parallel transmission techniques (dynamic/full pTx) exploit the amplitudes and phases of the multiple transmit channels as additional degrees of freedom to optimize the B₁⁺ field distribution or to tailor the spin magnetization in an ROI.³³ For pTx, typically not only all RF pulse shapes are optimized individually for each transmit coil element, but also the gradient trajectories are optimized. In addition, pTx techniques require 2-dimensional (2D) or 3-dimensional (3D) B₁⁺ field maps of each individual channel, which are a prerequisite for the determination of the pulse shapes and gradient trajectories. In early pTx implementations, the necessary preparation steps were complex and time-consuming. With the latest 7 T MR system, B₁⁺ shimming (static RF shimming) can be performed in a short time that does not significantly prolong the clinical workflow. However, the preparation steps for dynamic pTx are still time-consuming and can only be performed in research mode.

To avoid these calibrations before each measurement in vivo, so-called universal pulses were developed, which were optimized based on the B₁⁺ field maps of 6 subjects in the initial implementation. The resulting pulses can then be applied in other subjects without the need for calibration. This method significantly reduces the time needed before the actual measurement and thus offers great potential for future clinical application.³⁴ A recent approach combines universal pTx pulses and a fast subject-specific optimization for human brain MRI. This enables the calculation of individually optimized pTx pulses within a maximum of 15 seconds.³⁵

In general, dynamic pTx can be applied for global, slice-selective, or slab-selective excitation and for 2D or 3D selective excitation. A detailed overview on pTx techniques is given, for example, by Padormo et al.³³ In addition to inhomogeneities in B₁⁺ and B₁⁻, cancellations and hot spots can also occur in the local SAR distribution, which depends on the RF electric field pattern. This must be considered during the safety assessment; a detailed overview of this topic can be found in the review by Fiedler et al.²⁹ Therefore, there are currently hardly any commercial pTx body coils with regulatory approval available. Thus, a product pTx body coil, including safety aspects and SAR monitoring by the vendor, would greatly facilitate access to the torso at UHF.

Physical Characteristics of Nonproton MRS and MRI at UHF

Magnetic resonance data from nonproton nuclei with a nonvanishing nuclear spin such as phosphorus-31 (³¹P) and sodium-23 (²³Na) contain information about metabolic and functional processes that is highly valuable, as these nuclei are directly involved in many biological processes. In this section, the general physical properties of nonproton MRS and MRI at UHF are briefly discussed. A review of the detailed characteristics of each discussed nucleus as well as the relevant methods and clinical applications are given in the section X-Nuclei Magnetic Resonance Spectroscopy and Magnetic Resonance Imaging.

As with proton applications, nonproton MRS/MRI benefits from the increase in MR signal with B₀. Figure 1 shows that, at B₀ = 7 T, ²³Na MRI in the brain becomes achievable in clinically feasible measurement times.

FIGURE 1.

Sodium (²³Na) MRI at 1.5 (A), 3 (B), and 7 T (C). Images show that the SNR increases markedly with B₀. Sequence parameters: TE (1.5 and 3 T), 0.2 milliseconds; TE (7 T), 0.5 milliseconds; TR, 50 milliseconds; flip angle α, 77 degrees; nominal spatial resolution, 4 mm³; acquisition time, 10 minutes 50 seconds. Reused with permission from John Wiley & Sons, Kraff et al.³⁶

Spectroscopic nonproton applications, in common with ¹H MRS, additionally profit from the larger splitting of resonance frequencies in the MR spectrum. For example, at 7 T, it is possible to distinguish 2 resonances of inorganic phosphate in the ³¹P MR spectrum, the intracellular P_iⁱⁿ and the extracellular P_i^ex peaks.^37,38

Because of the fact that the Larmor frequency is nucleus-specific and depends on B₀, each combination of X-nucleus and field strength B₀ results in an individual resonance frequency (see section X-Nuclei Magnetic Resonance Spectroscopy and Magnetic Resonance Imaging). For a majority of X-nuclei, the resonance frequency at B₀ = 7 T or B₀ = 9.4 T is below 130 MHz (approximately ¹H at B₀ = 3 T or ³¹P at B₀ = 7 T) and thus much lower than 300 MHz. In contrast to ¹H MRI/MRS at B₀ ≥ 7 T, standing wave effects in the B₁⁺ field are negligible or manageable for X-nuclei MRI up to 130 MHz,³⁶ and standard RF coil designs can be suitable: (1) surface coils provide high B₁⁺ and B₁⁻ efficiency near the coil, which is advantageous for MRS, but the field distributions are inhomogeneous; (2) birdcage coils provide homogeneous field distributions over a large field of view, which is advantageous for concentration quantification of, for example, ²³Na and oxygen-17 (¹⁷O), but with the disadvantage of lower sensitivity.

However, for fluorine-19 (¹⁹F) spin excitation, the resonance frequency is roughly 280 MHz at B₀ = 7 T, and as with protons at B₀ ≥ 7 T, strong field inhomogeneities can occur during excitation in large samples. Therefore, dedicated excitation hardware and techniques are also required for ¹⁹F MRS/MRI in large samples at B₀ ≥ 7 T.

Magnetic resonance systems with B₀ = 7 T and higher do not have ¹H body coils installed because of the aforementioned problems with transmit homogeneity. Therefore, local dual-tuned RF coils that support ¹H MRS/MRI in addition to X-nuclei MRS/MRI can enable or simplify standard B₀ shimming as well as anatomical localization and coregistration. For a detailed discussion on nonproton MRS/MRI at UHF, please refer to the section X-Nuclei Magnetic Resonance Spectroscopy and Magnetic Resonance Imaging.

HIGH-RESOLUTION MORPHOLOGICAL MAGNETIC RESONANCE IMAGING

High-resolution proton MRI is still the major field for clinical applications at UHF. Static field strengths of 7 T provide higher SNR and in several applications higher CNR in comparison to MRI at lower field strengths that translates into increased resolution and improved differentiation among different tissue types. However, high-resolution MRI is consequently more prone to present motion artifacts, and particularly for inpatients and in the emergency department, motion is a common cause of MR image degradation.³⁹ Various prospective and retrospective motion correction methods are available that have been developed at lower field strengths.⁴⁰ At 7 T, ultrahigh-resolution images can be achieved applying motion correction.^41–43 The following sections provide an overview of important clinical applications of high-resolution imaging using UHF MRI.

Neuroradiology

There is a fast-growing body of evidence that particularly in the field of neuroradiology UHF MRI has the potential to aid diagnostics and clinical decision making. The increased resolution at UHF MRI improves depiction of anatomical substructures.^44–47 For instance, visualization of cranial nerves has been demonstrated at 7 T using magnetization-prepared rapid acquisition gradient echo (MPRAGE) and MP2RAGE MRI that could help diagnosis of cranial nerve disorders.⁴⁸

High-resolution morphological imaging has also been demonstrated feasible for the complex anatomical structures of the brain stem, including nonquantitative techniques (eg, T₂- and proton density–weighted imaging) and quantitative approaches, such as QSM, relaxation measurements (R₂*, R₁), and diffusion tensor imaging (Fig. 2).⁴⁹

FIGURE 2.

Susceptibility, R₁, R₂* maps, proton density-, T₂-weighted images, and color-coded diffusion anisotropy maps (left to right and top to bottom) of the same transverse slice in one healthy volunteer showing detailed anatomical substructures in the midbrain at 7 T and 3 T. A sagittal R₁ image indicates the slice location. Histologic myelin stain additionally shown for anatomical correlation (myelin stain reproduced from http://www.brains.rad.msu.edu and http://brainmuseum.org, supported by the US National Science Foundation). The cerebral aqueduct (CA), crus cerebri (corticobulbar fibers [cb], corticospinal fibers [cs], corticopontine fibers [cp]), the central tegmental tract (ctt), the mammillary body (MB), the medial lemniscus (ml), the medial longitudinal fasciculus (mlf), the optic tract (opt), the periaqueductal gray (PAG), the red nuclei (RN), the spinothalamic tract (stt), the substantia nigra (SN), the superiorcolliculus (SC), and the third ventricle (3 V) are indicated. The trochlear nuclei (TN) can only be clearly delineated in the histology stain. For better clarity, bilateral structures are only indicated monolaterally and at 7 T images. Reused with permission from John Wiley & Sons, Straub et al.⁴⁹

Generally, methods based on magnetic susceptibility MRI benefit strongly from strong magnetic fields.⁵⁰ Postprocessed phase images sensitive to magnetic susceptibility enhance the gray/white matter contrast.⁵¹ Susceptibility-weighted imaging can help to depict cerebral cavernous malformations⁵² and to further characterize white matter lesions.⁵³ Furthermore, MR venograms using deoxyhemoglobin (as an intrinsic contrast agent) can be obtained with very detailed information.⁵⁴ Magnetic resonance angiography (MRA) with 3D arterial TOF at UHF improves the visualization of small intracranial vessels and has the potential to better characterize vessel walls.^55,56 Seven Tesla MRI has also been demonstrated to enhance the depiction of small cerebral aneurysms and arteriovenous malformations (AVMs),^57,58 enabling the detection of microaneurysms with diameters ≤1 mm.⁵⁹ Dynamic information about the blood flow patterns within the AVM, for instance assessable via phase-contrast 4D flow MRI,^60,61 may further improve endovascular or surgical treatment planning in such diseases.

Magnetic resonance imaging is the most sensitive imaging technique to detect acute brain infarctions in patients with stroke.⁶² Minor ischemic infarcts were found by Novak and colleagues⁶³ using T₂-weighted gradient echo (GRE) and rapid acquisition with relaxation enhancement images at 8 T that were not detectable on routine MRI at 1.5 T. Moreover, cortical microinfarcts have been described using 7 T magnetization transfer (MT), which is only possible to a limited extent at 3 T.^44,64–66

In patients with brain cancer, MRI represents a cornerstone in diagnosis, treatment planning, and during follow-up.⁶⁷ Higher spatial resolution at 7 T could help to better differentiate infiltrative tumor from neighboring tissues^68,69 or to reduce the administered contrast agent dose because of increased CNR.⁷⁰ Furthermore, therapy-related changes in normal-appearing brain tissue may be better distinguished from residual or relapsing neoplasm.⁷¹ Neoangiogenesis of tumors can be visualized using 7 T TOF MRA, which could potentially be used to monitor response to antiangiogenic therapies.⁷²

In patients with multiple sclerosis (MS), better visualization of white matter lesions as well as the depiction of a central vein (“central vein sign”) and iron deposits within MS lesions have been described (Fig. 3).^46,73–75 Although several studies reported more lesions being detected at UHF compared with clinical field strength (1.5 T or 3 T), the literature is inconsistent regarding the diagnostic confidence for the diagnosis of MS using 7 T MRI.⁴⁶ Recent studies, however, reported growing evidence that 7 T has the potential to improve MS diagnosis.⁷⁶

FIGURE 3.

Axial T₂-weighted images of an MS patient acquired at 3 T (A) and 7 T (C) and corresponding axial SWI scans acquired at 3 T (B) and 7 T (D). Note the central vessels and iron deposits (rims) within MS lesions in SWI scans (B and D, white arrows). In T₂-weighted images, central vessels are challenging to depict (A and C, white arrows). Reused with permission from Wolters Kluwer Health, Inc, Springer et al.⁴⁶

In neurodegenerative diseases, more precise volumetric assessments of the hippocampal subfields and the entorhinal cortex can be performed at 7 T. Such investigations showed volume reductions in patients with Alzheimer disease (AD) in all hippocampal subfields and the entorhinal cortex compared with healthy controls and patients with mild cognitive impairment (MCI).^77,78 Microbleeds and white matter lesions are associated with vascular dementia. For this type of dementia, UHF MRI has been reported to yield improved sensitivity for an early diagnosis.^79,80

Loss of dopaminergic neurotransmission of the substantia nigra and tegmental area is associated with Parkinson disease (PD) and neuropsychiatric disorders. T₂*-weighted MRI and SWI acquired at UHF have been shown to allow better visualization of the substantia nigra and its inner organization,^81–83 which could aid target identification for deep brain stimulation.^84,85

In the neurologic assessment of patients with epilepsy, MRI is a highly sensitive modality for the identification of epileptogenic foci.⁸⁶ The gain in SNR and CNR at B₀ ≥ 7 T has been shown to improve the detection of possible epileptogenic zones, for example, focal cortical dysplasia, compared with MR scans at 3 T or 1.5 T.^87–92 Furthermore, better soft tissue contrast of the hippocampal architecture was achieved in patients with mesial temporal sclerosis at UHF MRI.⁸⁹ Investigations of hippocampal and temporal lobe volumes at 7 T revealed lateralization effects in patients with temporal lobe epilepsy.⁹³ The 7 T Epilepsy Task Force—an international group representing twenty-one 7 T MRI centers with experience from scanning over 2000 patients with epilepsy—has outlined the potential diagnostic value of 7 T MRI and provided guidance for appropriate clinical indications, patient selection, and radiologic guidelines for UHF MRI in patients with epilepsy.⁹² The clinical evidence of the added value of 7 T MRI for the management of patients with epilepsy is far beyond the current status of applications in other diseases. The 7 T Epilepsy Task Force could therefore serve as a role model for other fields, currently being investigated with 7 T.

Musculoskeletal Magnetic Resonance Imaging

Besides recent approval for clinical applications in neuroradiology, 7 T scanners have been approved for selected MSK applications in both the United States and the European Union.

High-resolution spin echo and GRE-based pulse sequences have been applied at 7 T to assess trabecular bone microarchitecture with improved visualization of anatomical substructures and quantitative measures of both bone volume fraction and marrow volume fraction (Fig. 4).^95–98 High spatial resolution is mandatory to visualize trabecular bone morphology, because the average diameter of the individual trabeculae is on the order of 100 to 150 μm.⁹⁴

FIGURE 4.

Magnetic resonance images of the distal tibia acquired in vivo with FIESTA-C at 7 T (A) and 3 T (B) are depicted. The enhanced visualization of trabecular bone structure at 7 T is well demonstrated by these images. Please note that, although the same sequence is used, chemical shift and susceptibility artifacts are enhanced at 7 T, shown by thicker appearing trabeculae and at the muscle/fat interface. Also, the image contrast and signal of muscle and fat are different at 7 T and 3 T. Reused with permission from Wolters Kluwer Health, Inc, Krug et al.⁹⁴

For ankle MRI, Juras et al⁹⁹ showed that both SNR (3D GRE) and CNR (2D turbo spin echo [TSE] and 2D GRE) significantly increase from 3 T to 7 T and therefore inferred a substantial diagnostic benefit using UHF. The diagnostic performance of 7 T versus 3 T in the detection of joint pathologies has been assessed by Springer et al¹⁰⁰ in 40 patients with knee pain. Besides significant gains in SNR (2D T₂ TSE, 2D TSE proton density, 3D dual-echo steady-state T₂), 7 T improved overall diagnostic confidence (semiquantitative assessment), particularly for fine structures in joints, as well as for subtle lesions in bone, menisci, and cartilage.¹⁰⁰ Furthermore, intermediate-weighted, fat-suppressed, fluid-attenuated inversion recovery MRI of the knee at 7 T has been demonstrated as a potential nonenhanced MRI method to visualize synovial inflammation in patients with psoriatic or rheumatoid arthritis.¹⁰¹

T₂ and T₂* mapping at 7 T have been applied to assess cartilage collagen matrix integrity and have been shown to positively correlate with water content.^102,103 Because of the increased resolution at UHF, both T₂ and T₂* MRI were less prone to partial volume effects than similar approaches at 3 T.¹⁰⁴ In addition, in vivo T₁-weighted delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) has been demonstrated to be feasible in healthy and reparative articular cartilage at 7 T MRI.¹⁰⁵ Zonal assessment of deep and superficial cartilage by means of dGEMRIC, T₂, and T₂* mapping may aid differentiation of healthy and affected articular cartilage in the future.¹⁰⁵

Diffusion tensor imaging has also been applied to assess cartilage matrix integrity through fractional anisotropy and the apparent diffusion coefficient. Raya et al¹⁰⁶ reported that both fractional anisotropy and apparent diffusion coefficient allowed distinguishing between healthy cartilage and cartilage affected by osteoarthritis.

T₁ρ imaging, which describes the relaxation of magnetization in the rotating frame, has been used to study proteoglycan content in cartilage. Magnetic resonance imaging at 7 T benefitted from increased SNR and chemical shifts compared with 3 T MRI, resulting in higher sensitivity to molecular changes at the same resolution.¹⁰⁷

Wei and colleagues¹⁰⁸ investigated knee cartilage pathologies with SWI at 7 T. They found that the arrangement of the collagen fibrils is the most dominant source of magnetic susceptibility anisotropy. Moreover, feasibility of QSM to characterize magnetic susceptibility properties of tissues in the knee joint has been demonstrated.¹⁰⁸ The authors inferred that QSM may be useful for evaluating the status of knee diseases, such as meniscal tears and cartilage disease, because of its sensitivity to collagen damage or degeneration.

Preliminary results of human spine MRI have been reported using multichannel transmit/receive phased array RF coils, demonstrating the feasibility of spine MRI at UHF.^109,110 Ultrahigh field human spine RF transceiver coil arrays face technical challenges in achieving large imaging coverage with sufficient B₁ penetration and sensitivity and in attaining robust decoupling among coil elements.¹⁰⁹ Comparisons of the diagnostic performance in lumbar spine MRI at 7 T versus 1.5/3 T could not prove superior imaging quality, so far precluding routine clinical use.¹¹¹ However, recent developments of novel coil technology (ie, 16-channel receive array as an add-on to multichannel transmit/receive RF coil configurations) have been demonstrated to increase SNR, lower g-factors, and thus improve 7 T spine MRI at 7 T.¹¹²

Different groups have demonstrated the feasibility of high-resolution cervical spinal cord MRI at 7 T, including multiparametric quantitative MRI,¹¹³ diffusion tensor imaging,¹¹⁴ and dynamic susceptibility contrast imaging.¹¹⁵ Three-dimensional dual-echo steady-state MRI at 7 T has been shown to allow precise assessment of the microanatomy of intraspinal cervical nerve roots.¹¹⁶

Abdominal and Thoracic Magnetic Resonance Imaging

Although the benefits of increasing field strength for neuroradiological and MSK applications have already been demonstrated in many cases, only few studies have so far investigated the potential of 7 T MRI for abdominal and thoracic MRI. Continuing developments in RF body coil technology and B₁⁺ shimming encourage the further exploration of UHF MRI in this area. Laader et al¹¹⁷ demonstrated that 7 T MRI showed partially comparable as well as both improved and inferior MRI results in the abdomen compared with lower field strengths, with substantial differences for T₁- and T₂-weighted MRI. Higher SNR and CNR were observed in multiple abdominal organs, potentially enabling detection of small pathologies that may be missed at lower field strength (Fig. 5).¹¹⁷

FIGURE 5.

Three-dimensional VIBE MRI at 1.5 T (A), 3 T (B), and 7 T (C) in the same subject. Seven Tesla 3D VIBE MRI demonstrated diagnostic potential by means of pathology detection, as it revealed a second hemorrhaged renal cyst (dashed arrow C₁) not displayed at lower field strengths. In the second row, arrows show a further very small renal cyst in the same subject, which is also best visible at 7 T (C₂). Reproduced with permission, open access, Laader et al.¹¹⁷

Umutlu et al¹¹⁸ demonstrated that 7 T MRI of the kidneys is feasible providing good overall image quality, particularly for T₁-weighted GRE MRI. T₂-weighted TSE and TrueFISP MRI were limited at 7 T because of artifacts and SAR restrictions. Fischer et al¹¹⁹ demonstrated feasibility of contrast-enhanced MR cholangiopancreatography at UHF. Results were evaluated as equivalent but not superior in comparison to 3 T MR cholangiopancreatography, that is, because of residual B₁ field inhomogeneities.¹¹⁹

Prostate MRI in clinical routine mainly relies on T₂-weighted MRI and DWI (± dynamic contrast-enhanced MRI). High-resolution T₂-weighted TSE MRI of the prostate for improved delineation of prostate anatomy has been demonstrated and applied in patients with prostate cancer using an 8-channel transmit/receive RF body array.^120,121 Cancer lesions in both peripheral zone and transition zone were delineable at 7 T.¹²¹ Multichannel endorectal coil have been proposed for use in combination with an external surface array for high-resolution anatomical and functional studies of the prostate at 7 T.¹²² For the assessment of pelvic lymph nodes (eg, for the evaluation of metastatic disease), feasibility of high-resolution USPIO-enhanced MRI has been demonstrated at 7 T.¹²³

Bilateral RF breast coils are mandatory to achieve high spatial resolution and high contrast in breast MRI applications at 7 T.¹²⁴ In patients with breast cancer, dynamic contrast-enhanced breast MRI,¹²⁵ DWI,¹²⁶ and multiparametric approaches^127,128 have been proven feasible in clinical settings with the potential to improve diagnostic accuracy.

Technical feasibility of 7 T cardiac MRI has been demonstrated using steady-state free precession and fast gradient echo sequences for cardiac cine MRI.^129–132 Generally, residual B₁ field inhomogeneities and the consequent need for further development of RF coils and pTX optimization are challenges that need to be addressed by researchers and manufacturers. Schmitter et al¹³³ combined pTX and simultaneous excitation of multiple slices (from a limited number of slices during breath-hold) to reduce contrast heterogeneity while allowing larger slice coverage in cardiac MRI at 7 T.

X-NUCLEI MAGNETIC RESONANCE SPECTROSCOPY AND MAGNETIC RESONANCE IMAGING

Besides protons, other nuclei with a nonvanishing nuclear spin can also be detected by MRS/MRI. Magnetic resonance applications of these nuclei are termed X-nuclei, nonproton, or multinuclear MRI/MRS applications. General physical properties of nonproton MRS and MRI at UHF are briefly described in the section Physical Characteristics of Nonproton MRS and MRI at UHF. In the following subsections, the nucleus-specific characteristics, methods, and clinical applications are described.

In general, the strength of these X-nuclei MR methods is that they are able to provide information that cannot be obtained with conventional proton MRI; for example, they directly provide insights into energy substrates and pH,¹³⁴ ion balance,¹³⁵ and cerebral oxygen turnover.¹³⁶

However, low sensitivities and/or low in vivo concentrations of X-nuclei, along with other nuclei-specific properties (see following sections), pose challenges for X-nuclei MRI/MRS. Consequences are generally long measurement times, low spatial resolutions on the order of several mm³, and partial volume effects. A summary of general MR properties for different X-nuclei is given in Table 1. The MR signal S depends on the nucleus-specific quantities spin I, gyromagnetic ratio γ, natural abundance α, and on the in vivo concentration c as follows.

TABLE 1.

Overview of the Nucleus-Specific Properties of Commonly Used X-Nuclei in MRI/MRS, Including the Spin Ι, the Gyromagnetic Ratio γ, and the Natural Abundance α

Nucleus	Ι, ℏ	$\frac{\gamma }{2\pi }$, MHz/T	α, %	Relative Sensitivity, %	Relative Signal
1H	1/2	42.6	99.99	100	1
2H	1	6.5	0.015	0.0001	10−6
13C	1/2	10.7	1.07	0.017	10−5
17O	5/2	−5.8	0.04	0.0012	10−5
19F	1/2	40.1	100	83.4	10−5
23Na	3/2	11.3	100	9.25	10−5–10−4
31P	1/2	17.3	100	6.63	10−6
35Cl	3/2	4.2	75.78	0.356	10−5
39K	3/2	2.0	93.26	0.0473	10−5

The relative sensitivity of the X-nuclei compared with conventional proton sensitivity is given as well as the relative sensitivity strength (see Equation 1), where the in vivo concentration was additionally accounted for. Table modified from Niesporek et al.¹³⁷

$$S~I\left(I+1\right)·{\gamma }^3·\alpha ·c$$ (Equation 1)

Unlike proton MRI/MRS, X-nuclei applications have thus far not been established clinically at conventional field strengths of 1.5 T or 3 T, so there is a fundamental opportunity to translate X-nuclei MRI/MRS into clinical use at UHF. At least one manufacturer has secured regulatory approval for both ³¹P spectroscopy/spectroscopic imaging for the whole body excluding the head and ²³Na imaging of the head at 7 T.¹³⁸ However, X-nuclei MRS and MRI techniques are currently applied almost exclusively in research studies.

Phosphorus-31 Magnetic Resonance Spectroscopy

Phosphorous (³¹P) is a spin-1/2 nucleus, and thus, ³¹P MRS enables the detection of energy substrates such as phosphocreatine (PCr), adenosine triphosphate (ATP), adenosine diphosphate, and inorganic phosphate (P_i). In addition, the resonances of phosphocholine, phosphoethanolamine, glycerophosphocholine, and glycerophosphoethanolamine provide insights into the cellular and mitochondrial membranes.¹³⁹ Consequently, valuable information about the energy and membrane metabolism can be obtained from a ³¹P spectrum.

Because of the increasing influence of chemical shift anisotropy on the relaxation mechanisms, a decrease in phosphorous T₁ relaxation time with increasing field strength was observed in the human calf for 7 T versus 3 T, which can allow shorter measurement times or additional SNR per unit time at higher field strengths.¹⁴⁰ In addition, the nuclear Overhauser effect (NOE) and decoupling can be used to increase the SNR and to simplify the spectrum. However, UHFs complicate these approaches because of the required high-power deposition, and therefore SAR issues, as well as the inhomogeneities in the ¹H B₁⁺ field.¹⁴¹

Furthermore, the absolute pH value can be calculated from the distance between the PCr resonance and the P_i resonance in the ³¹P spectrum, which enables mapping of the pH value.^142,143 In recent years, it has been shown that, with the higher spectral resolution at B₀ ≥ 7 T, it is possible to detect 2 P_i signals: the intracellular P_iⁱⁿ and the extracellular P_i^ex.^37,38 Although quantification of extracellular pH is challenging because of the low SNR in vivo, recent studies have shown that determination of both intracellular and extracellular pH in the human brain is feasible using ³¹P MRS at 7 T.¹⁴⁴

So far, several studies have been performed in small cohorts in the brain as well as in the calf muscle,^139,145 where it was demonstrated, for example, that UHF ³¹P MRS enables the investigation of the creatine kinase rate, ATP synthesis rate, and nicotinamide adenine nucleotide (NAD⁺, NADH).^38,146–149

The development of ³¹P volume coils^150–152 or dedicated ³¹P coils for specific body regions^153–155 for 7 T ³¹P MR applications enables valuable insights into body regions beyond the head, with increased SNR and spectroscopic resolution. A first human cardiac ³¹P spectrum at 7 T¹⁵⁶ showed that SNR of every peak increases compared with 3 T, for example, the SNR of PCr increased by factor of 2.8.

However, up to now, ³¹P MR studies in patients have mainly been performed at field strengths below 7 T. This may be because of the limited availability of UHF scanners, which may change with the increase in the number of 7 T MR systems and with the distribution of 7 T MR systems as a medical device enabling ³¹P MRS/MR spectroscopic imaging (MRSI) for the whole body excluding the head.¹³⁸

Neuroradiology

A large number of studies have dealt with ³¹P MRS in neurological diseases, for example, in PD, where mitochondrial dysfunction and alterations of membrane phospholipid metabolism were observed at 1.5 and 3 T.^157–161 However, metabolic changes in early and mildly affected PD patients could not be detected reliably at 3 T.¹⁶² Abnormal phosphate metabolite and ion concentrations were detected in multisystemic atrophy via ³¹P MRS; thus, ³¹P MR applications might enable the differentiation between multisystemic atrophy and PD.¹⁶³ Moreover, in mild AD, increased PCr and pH were observed,¹⁶⁴ and in patients with epilepsy, alterations in mitochondrial function were detected via ³¹P MRS.^165,166

The higher SNR and the higher spectral resolution at UHF offer great potential for investigating neurological diseases via ³¹P MR applications. For example, abnormal energy metabolism in cortical brain region of PD patients was demonstrated with ³¹P MRS at 7 T.¹⁶⁷

At 9.4 T, high-resolution pH mapping with a nominal voxel size of 15 mm³ was performed in the healthy human brain as well as in patients with brain tumors.¹³⁴ Recently, the feasibility of volumetric mapping of intracellular as well as extracellular pH in patients with brain tumors was demonstrated at 7 T (Fig. 6), offering the potential to provide new insights into the pH heterogeneity of different tissues, especially in tumor tissues.¹⁴⁴

FIGURE 6.

Axial intracellular and extracellular pH maps in 3 patients with glioma merged with nonenhanced T₁-weighted MPRAGE (black/blue boxes: manually segmented tumor ROIs within the solid tumor compartment). Reused with permission from John Wiley & Sons, Korzowski et al.¹⁴⁴

Body Applications

³¹P MRS in the liver has been applied in a broad spectrum of pathologies, including viral and alcoholic liver disease, nonalcoholic fatty liver, cirrhosis, diabetes, insulin resistance, and liver metastases at 1.5 and 3 T.¹⁴⁵ The feasibility of ³¹P MRS in the human liver was also demonstrated at 7 T,^168–170 and patients with liver cirrhosis examined at 7 T showed significantly lower P_i and phosphatidylcholine concentrations and significantly higher glycerophosphoethanolamine concentrations.¹⁷¹

The application of high-field ¹H MRI and ³¹P MRSI in human breast at 7 T enables the investigation of phospholipid metabolism, phosphate energy metabolism, and intracellular pH in addition to standard ¹H applications.¹⁷² At 7 T, altered levels of ³¹P metabolites in breast tissue were observed in tumor patients compared with healthy volunteers, and levels were modulated during neoadjuvant chemotherapy.¹⁷² Preliminary results from ³¹P MRS at 7 T and subsequent biopsy show that higher numbers of mitosis (proliferation marker) correspond to higher relative concentrations of PME (PME/PDE) in the ³¹P spectrum.¹²⁸

In the human prostate, combined ¹H and ³¹P MRSI is feasible at 7 T, which allows, for example, a detailed study of the choline (Cho) metabolism, with negligible efficiency losses in ¹H MR because of the combined acquisition of ¹H and ³¹P.¹⁵³ Furthermore, a recent study demonstrated the feasibility of ³¹P MRS in lung carcinoma at 7 T, which may have the potential to be used in addition to standard methods for noninvasive monitoring of treatment response in lung tumors.¹⁷³ In dynamic ³¹P MRS of the lower leg at 7 T, differences in PCr resynthesis rates could be detected between healthy volunteers and a diabetic patient.¹⁷⁴

In conclusion, ³¹P MR applications at UHF represent a very promising method that may provide new physiological insights in the future.

Sodium-23 Magnetic Resonance Imaging

Sodium-23 is a spin-3/2 nucleus that exhibits the second highest MR signal in the human body among the MR-detectable nuclei. Especially with increasing availability of UHF MR scanners, the potential of ²³Na MRI has increased because of the linear SNR increase with B₀, which is expected for resonance frequencies at least up to approximately 64 MHz (see section Physical Challenges and Advantages of Ultrahigh Field).

Sodium plays a crucial role in many physiologic processes such as the maintenance of cell homeostasis, transmission of action potentials, and regulation of pH, blood volume, and blood pressure. In healthy excitable cells, the concentration of sodium ions in the intracellular space is 5 to 15 mmol/L and in the extracellular space 140 to 150 mmol/L.^137,175 This concentration gradient is maintained, among others, by the sodium-potassium pump (Na⁺-K⁺-ATPase). Therefore, impairment of energy metabolism or disruption of cell membrane integrity will affect the concentration gradient. Determination of sodium concentrations by ²³Na MRI can thus provide information about the tissue state.¹⁷⁵

Consequently, ²³Na MRI offers a variety of applications for investigating physiologic and pathophysiologic processes in the human body. Comparable to ³¹P MR applications, many studies have been performed so far in the head and calf muscle. Here, Staroswiecki et al¹⁷⁶ demonstrated a 2.3-fold higher SNR in the cartilage at 7 T compared with 3 T, which is in accordance with the expected linear increase in SNR with B₀. With the development of ²³Na volume coils^177–179 or dedicated ²³Na coils for specific body regions,¹⁸⁰ valuable insights into the torso could also be achieved with ²³Na MRI.^181–184

Neuroradiology

A large number of studies have shown that ²³Na MRI is well suited for the investigation of neurodegeneration and neuroinflammation, tumors, energetic imbalances, and excitability disorders.¹⁸⁵

²³Na MRI in MS at a field strength of 3 T demonstrated increased tissue sodium concentration (TSC) in acute and chronic lesions but also in normal-appearing white matter compared with healthy controls.¹⁸⁶ A recent study at 7 T further showed a widespread distribution of increased TSC in various MS gray and white matter regions,¹⁸⁷ which complements results obtained at 3 T.¹⁸⁸

In further studies, a correlation among brain sodium accumulation and disability,^188,189 disease progression,¹⁸⁹ cognitive impairment,¹⁹⁰ and lesion evolution¹⁹¹ was detected. Furthermore, sodium was found to be a promising tool to monitor patients with progressive MS.¹⁹² A recent study showed that intralesional heterogeneity could be observed when using high-resolution ²³Na MRI if the lesion is of sufficient size.^193,194 More advanced techniques applying triple quantum filtered ²³Na MRI¹⁹⁵ provide information about the intracellular sodium concentration and the intracellular volume fraction in MS.¹⁸⁷ The feasibility of triple quantum filtered ²³Na MRI at 7 T was also demonstrated in patients with MS.¹⁸⁷

A multitude of further cerebral diseases has been explored with ²³Na MRI, including Huntington disease (HD),¹⁹⁶ AD,¹⁹⁷ cerebral infarction,¹⁹⁸ migraine,¹⁹⁹ and epilepsy.²⁰⁰

Furthermore, ²³Na MRI has been applied to cerebral tumors, where, for example, brain tumor growth could be monitored.²⁰¹ The TSC is increased in brain tumor tissue.²⁰² Hence, ²³Na MRI has been investigated for characterizing tumor proliferation²⁰³ and therapy response.²⁰⁴ Recently, the correlation between TSC and isocitrate dehydrogenase (IDH) mutation status was demonstrated at 7 T.²⁰⁵ Thus, the spatially resolved information from ²³Na MRI could assist in determining biopsy sites as well as in surgery and radiation therapy.²⁰⁵

With the availability of 7 T MR systems as a medical device enabling ²³Na head imaging at 7 T by at least 1 vendor,^{138 23}Na MRI with its increased SNR at UHF offers great potential for future studies in larger patient cohorts.

Body Applications

Beyond these neurological applications, a variety of body regions and disease conditions have been investigated in initial feasibility studies using ²³Na MR.

²³Na MRI offers the special possibility of gaining additional insight into the condition of the cartilage, for example, in the knee, because it is sensitive to the glycosaminoglycan (GAG) content.²⁰⁶ Thus, ²³Na MRI at 7 T can provide insights into cartilage health, repair tissue, and treatment response, for example, in osteoarthritis without the need for a contrast agent.²⁰⁶ For example, after matrix-associated autologous chondrocyte transplantation, ²³Na MRI enabled a differentiation of repaired tissue from native cartilage, and a correlation was found between ²³Na MRI and dGEMRIC.

Furthermore, ²³Na MRI was investigated in various diseases in which a change in the distribution of muscular ²³Na concentrations is to be expected, for example, in Duchenne muscular dystrophy,^207,208 in dialysis patients,²⁰⁹ and in diabetic patients.^210,211

A 7 T ²³Na MRI study in patients with periodic paralysis demonstrated higher muscular ²³Na concentration than in healthy volunteers.²¹² Consequently, sodium homeostasis can be visualized in periodic paralysis at 7 T and might be used to evaluate new therapies.

In addition, in both chronic myocardial infarction and after acute myocardial infarction, increased ²³Na signal has been shown in infarcted nonviable myocardium,^181,213,214 and recent methodological work showed that corrections are necessary in ²³Na cardiac MRI to quantitatively estimate concentration values in the myocardium at 7 T.¹⁸⁴

Furthermore, renal ²³Na MRI has been performed under various physiological conditions, for example, after radiation therapy and after renal transplantation.^183,215,216 Because sodium plays a very important role in renal physiology, ²³Na MRI provides the opportunity to investigate whether kidney function is normal or if any pathological alterations exist.^217,218 Preliminary results of renal ²³Na MRI at 7 T²¹⁹ showed the feasibility of an increased spatial resolution with a nominal in-plane resolution of 4 × 4 mm² and a slice thickness of 5 mm compared with studies at 3 T with nominal spatial resolutions of 3 × 3 × 15 mm^3218,220 and 5 × 5 × 5 mm³.²¹⁵

Recent studies on quantitative ²³Na breast MRI at 7 T showed good differentiation between malignant and benign breast lesions and the potential to predict early treatment outcomes of neoadjuvant chemotherapy, with reduced TSC indicating therapy response.^221,222 Further ²³Na studies have investigated lung cancer²²³ and prostate tumors.²²⁴

Hence, ²³Na MRI offers diverse research opportunities, and the reasonable spatial resolutions within clinically feasible measurement times at UHF offer the possibility of bringing these applications into clinical use.

Further Exotic X-Nuclei

Potassium-39 and Chlorine-35 Magnetic Resonance Imaging

As with ²³Na MRI (see section Sodium-23 Magnetic Resonance Imaging), MRI of potassium-39 (³⁹K) and chlorine-35 (³⁵Cl) provides insight into ion balance in humans. These 2 nuclei, in common with ²³Na, have a nuclear spin of 3/2 and undergo quadrupole interaction, which leads to even shorter relaxation times at 7 T compared with ²³Na,^225–227 and because of the even lower MR sensitivity (see Table 1), UHF MRI was needed to pioneer the MRI of ³⁹K and ³⁵Cl, with first human applications in the brain and muscle of healthy volunteers.^{225,227–229}

Applying ³⁵Cl MRI at 7 T, pathophysiological changes of Cl⁻ homeostasis were demonstrated in patients with a tumor and in muscular ion channel disease.²²⁵ Wenz et al²³⁰ recently demonstrated for the first time the feasibility of ³⁹K MRI of the human heart. This is a very interesting research application, because potassium ions play a crucial role in cardiac electrophysiology, and pathophysiological processes are expected to lead to changes in myocardial ³⁹K concentration. These initial feasibility studies demonstrate the great potential of X-nuclei MRI at UHF to noninvasively gain insight into ion balance inside the living organism.

Tracer Nuclei: Oxygen-17, Deuterium, Carbon-13, and Fluorine-19

Several X-nuclei can be used as tracers to monitor metabolic pathways because of their low natural abundance and/or low in vivo concentrations.

Oxygen-17 is a nontoxic and stable oxygen isotope with a nuclear spin of 5/2. Thus, it can be detected by means of ¹⁷O MRI. Because the natural abundance of ¹⁷O is just 0.038%, this isotope can be used as a tracer. When ¹⁷O MR data are obtained while inhaling enriched ¹⁷O₂ gas, these dynamic data enable insights into cerebral oxygen turnover. By fitting a metabolic model¹³⁶ to the dynamic H₂¹⁷O signal, the cerebral metabolic rate of oxygen consumption (CMRO₂) can be determined in different tissues such as the gray matter, white matter, and tumor tissue.²³¹ Hence, ¹⁷O MRI is a promising research technique for the direct investigation of cerebral oxygen metabolism. However, dedicated hardware and acquisition techniques are essential, and the gas is quite expensive. Hence, only a limited number of studies have been performed with ¹⁷O MRI in humans up to now, all limited to ¹⁷O brain MRI.

Hoffmann et al²³² obtained the first dynamic ¹⁷O MR data in a patient with glioblastoma, showing a decreased CMRO₂ value within the tumor tissue. Recently, a ¹⁷O inhalation study including 10 patients with brain tumors was published²³³ in which both high-grade and low-grade gliomas exhibited a lower ¹⁷O MR signal increase in the tumor region and a decrease in tumor CMRO₂, which is in accordance with the Warburg effect.

Deuterium (²H) has a nuclear spin of I = 1 and a very low natural abundance. Consequently, deuterium metabolic imaging (DMI) enables the investigation of metabolism in vivo through ²H MRS/MRSI before and after uptake of ²H-labeled substrates.^234,235 This novel noninvasive approach was demonstrated in animals^236–239 as well as in healthy volunteers and patients with glioblastoma at B₀ = 4 T²³⁴ and has attracted increasing interest from several research groups.^240,241 Recently, it was shown that the sensitivity of DMI increases supralinearly with B₀ for small animal coils between 4 and 11.7 T and for larger human coils between 4 and 7 T.²⁴² According to de Graaf et al,²⁴² the improved sensitivity at 7 T enables the acquisition of 3D DMI data at a nominal 1 mL spatial resolution. Consequently, DMI is a promising application especially at UHF, where it benefits from the increased SNR and spectral resolution.²⁴²

Carbon-13 (¹³C) is a constituent of almost all biochemically relevant molecules, and because of its low natural abundance, it can be administered to trace metabolic pathways.^243,244 Heteronuclear coupling can be addressed with ¹H decoupling, which collapses multiplets into a singlet resonance and results in an increased SNR and simplification of the spectrum. In general, heteronuclear decoupling is challenging, because it requires transmitting at the ¹H frequency while receiving the very low NMR signal at the ¹³C frequency, requiring highly adapted and optimized hardware. Ultrahigh field complicates heterogeneous broadband decoupling because of the high-power deposition (SAR) and the inhomogeneities in the ¹H transmit field.²⁴⁵ Nevertheless, the feasibility of heteronuclear ¹H decoupling of ¹³C spectra has been demonstrated in humans in vivo at 7 T.²⁴⁵ In a ¹³C MRS study at 7 T, patients with glycogen storage disease showed a 2.5-fold increase in muscle glycogen concentrations²⁴⁶; these results were also consistent with muscle needle biopsy results. Thus, noninvasive ¹³C MRS could support diagnosis of glycogen storage disease or therapy monitoring.

The NMR properties of ¹⁹F are comparable to those of protons, leading to a relative sensitivity of 83% compared with ¹H. However, the abundance of ¹⁹F in the human body is very low. Thus, fluorinated exogenous compounds can be administered and detected as a tracer, offering high specificity. Up to now, ¹⁹F MR applications have been limited to in vitro or animal experiments.²⁴⁷ Studies have investigated, among others, the macrophage response in inflammatory processes²⁴⁸ or after cerebral infarction.²⁴⁹ Because fluorine has a similarly high resonance frequency as ¹H (see Table 1), hardware and acquisition techniques for ¹⁹F MRI in humans at 7 T need to be adapted to overcome challenges such as inhomogeneities in the transmit field (see section Radiofrequency Characteristics of ¹H at Ultrahigh Field: Issues With Field Inhomogeneity).

PROTON MAGNETIC RESONANCE SPECTROSCOPY

Proton MRS is used for the direct measurement of metabolites, neurotransmitters, and tissue compositions, all noninvasively. In general, ¹H MRS and MRSI at UHF benefit from the increased SNR, larger frequency dispersion, and reduced J-coupling in strongly coupled spin systems.¹³⁹ Consequently, various metabolites can be detected, distinguished, and quantified more precisely.²⁷ However, inhomogeneities in B₀, B₁⁺, B₁⁻, and SAR at UHF present challenges (see section Physical Challenges and Advantages of Ultrahigh Field) and necessitate new hardware and acquisition techniques.^{26,139,250–255} To further improve spectrum quality, both retrospective and prospective motion correction have been suggested.²⁵⁶

A detailed overview on advantages, challenges, and advances of UHF ¹H MRS/MRSI is given by Henning¹³⁹ and by Ladd et al¹⁷ (section 7). In the following subsections, advances in ¹H MRS/MRSI applications at UHF in the brain and body are discussed.

Neuroradiology

Feasibility of single voxel ¹H MRS at 7 T to resolve spectral patterns of more than 15 brain metabolites, for example, myo-inositol and taurine and overlapping multiplets of J-coupled spin systems, such as glutamine and glutamate (Glu), has been demonstrated by Tkác and colleagues²⁶ in healthy subjects. Using single voxel ¹H MRS at 7 T, studies have reported sufficient sensitivity to detect changes caused by functional activity (eg, visual stimulation) for concentration changes greater than 0.2 μmol/g at 7 T.

In patients with glioma, 7 T MRI extends the available metabolite maps compared with 3 T approaches, which allows the assessment of an extended neurochemical profile in shorter acquisition time.²⁵⁷ Because of the critical relevance of the IDH mutation status for diagnosis and prognosis of patients with glioma, strong efforts have been made to develop MRI approaches to identify the IDH mutation status noninvasively.²⁵⁸ Magnetic resonance spectroscopy of 2-hydroxyglutarate (2-HG) has gained considerable attention, because the oncometabolite 2-HG is known to accumulate in gliomas with mutations in the IDH1/2 genes. At 3 T, detection of 2-HG has been demonstrated to be feasible but remains challenging in clinical practice.²⁵⁹ Therefore, 2-HG MRS at 7 T with increased SNR and spectral resolution could be capable of differentiating IDH mutation from wildtype brain tumors more reliably without the need for invasive procedures.²⁶⁰

In patients with MS, MRS biomarkers such as glutathione, γ-aminobutyric acid, Glu, and others demonstrated the potential of UHF MRI to aid lesion characterization that could help in clinical decision making.²⁶¹

Seven Tesla MRS has also been applied in patients with amyotrophic lateral sclerosis, showing decreased N-acetylaspartate (NAA) and Glu in subjects with amyotrophic lateral sclerosis compared with healthy controls.²⁶² The study findings indicate neuronal injury and/or loss in the precentral gyrus associated with the disease.

Investigations of 7 T MRS in patients with HD revealed decreased concentrations of NAA and creatine in the caudate nucleus and putamen of early manifest HD, suggesting deficits in neuronal integrity and energy metabolism.²⁶³

In patients with AD, 7 T MRS revealed several region-specific effects of MCI on brain metabolite levels.²⁶⁴ In a pilot study, Oeltzschner et al²⁶⁴ found MCI to be associated with decreased γ-aminobutyric acid and Glu levels, most consistently in the posterior cingulate cortex.

Magnetic resonance spectroscopic imaging at UHF offers the possibility to assess region-specific heterogeneity of metabolic profiles in various diseases. The introduction of ultrashort echo time sequences, such as, for example, free induction decay (FID) MRSI, aids avoiding SNR loss because of short T₂ relaxation.^265,266 Free induction decay MRSI has therefore improved detectability of low concentration metabolites at higher spatial resolutions.^265,266 Comparison of spectral quality of high-resolution FID MRSI at 3 T and 7 T demonstrates clear improvement in spectra quality and quantification precision for 7 T FID MRSI (Fig. 7).²⁶⁷

FIGURE 7.

Sample spectra overlaid with the LCModel fit (red color) at 3 T (left column) and 7 T (right column) from 3 different locations: occipital lobe (top), frontal lobe (middle), and parietal lobe (bottom). For instance, note the tNAA signal at 7 T. The better spectral resolution allows differentiation of NAA and NAAG at 7 T, but not at 3 T (measurement parameters: excitation flip angle, 45 degrees; field of view, 220 × 220 mm²; 64 × 64 matrix; TR, 600 milliseconds; TE*, 1.5 milliseconds; bandwidth, 6000 Hz; 2048 points; and 10-mm slice thickness). Reused with permission from Wolters Kluwer Health, Inc, Gruber et al.²⁶⁷

At 9.4 T, high-resolution metabolite maps (97 μL nominal voxel size, 18 brain metabolites) have been acquired by Nassirpour et al²⁶⁸ by combining an improved sensitivity encoding (SENSE) reconstruction with a B₀ correction of spatially overdiscretized MRSI data. With SENSE and GRAPPA, entire k-space lines are omitted. To achieve higher accelerations compared with 2D parallel imaging methods in multislice MRSI, the 2D CAIPIRINHA approach has been suggested, where k-space points are skipped in arbitrary patterns.²⁶⁹ Furthermore, spatial-spectral encoding (eg, rings, spirals) yields high acceleration factors of up to 2 orders of magnitude.²⁷⁰

Hingerl and colleagues²⁷¹ applied FID MRSI with a rapid concentric ring trajectory at 7 T for metabolic mapping of the whole cerebrum (8 metabolites) in healthy subjects, 1 patient with glioma and another patient with MS. In tumor tissue, Cho, glutamine, and glycine were markedly increased compared with normal-appearing brain regions.²⁷¹

Hangel et al²⁷² combined MRSI with patch-based superresolution reconstruction for high-resolution multimetabolite mapping of gliomas and demonstrated metabolic activities beyond morphologically visible deviations.

The previously discussed role of the oncometabolite 2-HG in IDH-mutant gliomas has also motivated the development of 3D MRSI targeting 2-HG, for example, using MEGA (Mescher-Garwood) and LASER (localization by adiabatic selective refocusing).^273,274 Andronesi et al²⁷⁴ showed that 3D dynamic measurements of 2HG are feasible, and that changes in IDH associated with therapy response can be monitored in patients with IDH-mutant gliomas. The monitoring of treatment response and patient follow-up is of particular interest for the application of imaging biomarkers in cancer, because serial biopsies are usually not feasible.

Body Applications

Seven Tesla MRS has the potential to become an important tool in clinical MSK MRI because of its noninvasive sensitivity to metabolic tissue features.

Investigations of lipid metabolism of the human calf muscle at 7 T showed accurate and reliable spectroscopic examination by both 1D and 2D MRS.²⁷⁵ Estimates of intramyocellular lipids and extramyocellular lipids could be improved by including variations in fiber orientation in the lineshape analysis.²⁷⁶ The 2D approach has offered improved resolution and sensitivity compared with previous reports at lower field strength and improved opportunities to study disease effects in muscles.²⁷⁵

The feasibility of prostate ¹H MRSI at 7 T has been demonstrated by Lagemaat et al,²⁷⁷ who used a low-power spectral-spatial pulse sequence while using separate transmit and receive coils. The low-SAR MRSI concept provided the opportunity to increase spatial resolution of MRSI within reasonable scan times.²⁷⁷

Breast ¹H MRS at 7 T has been investigated in a pilot study by Korteweg et al²⁷⁸ using a 2-channel coil setup. The obtained spectra in patients with breast cancer showed a decrease in Cho concentrations during neoadjuvant chemotherapy, suggesting responsiveness to treatment.²⁷⁸

FUNCTIONAL MAGNETIC RESONANCE IMAGING FOR MAPPING NEURONAL ACTIVITY

Mapping neuronal activity in the human brain can be performed via so-called fMRI. As standard, the BOLD (blood-oxygen-level-dependent) effect is used for this purpose, which exploits the fact that oxyhemoglobin (oxygenated hemoglobin) is diamagnetic, whereas deoxyhemoglobin (deoxygenated hemoglobin) is paramagnetic.^279–281 Neuronal activity leads to increased oxygen consumption, which is overcompensated by an increased cerebral blood flow. As a result, more oxyhemoglobin is present during activation, which causes fewer susceptibility-induced field perturbations in the local magnetic field, leading to reduced spin dephasing and a lower relaxation rate R₂*. Consequently, the signal in activated brain regions is higher in T₂*- and T₂-weighted MR images. As mentioned in the section Physical Challenges and Advantages of Ultrahigh Field, higher magnetic fields provide increased susceptibility sensitivity and thus also an enhanced BOLD effect.^282,283

Because of the expectation of a supralinear increase in BOLD sensitivity²⁸⁴ as well as improved spatial localization²⁸⁵ with static magnetic field strength, fMRI represents one of the driving forces in the development of UHF systems.^286,287 However, poorer static magnetic field homogeneity and poorer B₁⁺ homogeneity complicate fMRI at UHF. Here, the use of pTx can lead to a significant improvement. A detailed overview on the underlying biophysics of the BOLD contrast as well as on pulse sequences and applications at UHF is given by Marques and Norris²⁸⁸ and by Ladd et al¹⁷ (section 9).

Neuroradiology

The spatial resolution at 3 T is limited to approximately 2 mm³, whereas at 7 T, a resolution of approximately 1 mm³ can be achieved.²⁸⁹ Submillimeter resolutions were also obtained at 7 T, for example, 0.65 mm³ for visual stimulation and 0.75 mm³ for sensorimotor stimulation.²⁹⁰ Thus, UHF fMRI enables improved mapping of neuronal activity in the cortex,^291,292 cerebellum,^293,294 and subcortical structures.^295,296 Recently, a submillimeter resolution of 0.75 mm³ was achieved in resting state fMRI while applying the method to a macaque at a field strength of 10.5 T.²⁸⁷

Comparing 3 T to 7 T fMRI, a study in 17 patients showed that a simple motor task resulted in increased activation in the primary motor cortex at 7 T. However, ghosting and motion artifacts were more prevalent at 7 T.²⁹⁷

In addition to the main applications of UHF fMRI to study neuronal activity at high spatial resolution, further promising areas of research are focused on fMRI of the cortical layers and columns.^298–302 Thus far, however, UHF fMRI has been less extensively evaluated for clinical application, for example, for presurgical planning.^303,304

CHEMICAL EXCHANGE-SENSITIVE MAGNETIC RESONANCE IMAGING

Chemical exchange-sensitive MRI techniques are based on the chemical exchange between solute-bound protons and protons of free bulk water. One type of chemical exchange-sensitive MRI that has recently gained considerable attention is CEST MRI.³⁰⁵ Chemical exchange saturation transfer MRI permits large signal amplification of low-concentration molecules in vivo. The amide proton transfer (APT) effect is most commonly assessed with CEST MRI. Amide proton transfer effects resonate at approximately +3.5 parts per million relative to the water proton resonance. Amide proton transfer signal quantification is usually achieved using the MT ratio asymmetry approach proposed by Zhou et al.³⁰⁶ By providing information on protein concentration and microenvironmental tissue features, CEST MRI extends the available repertoire of MR biomarkers in diagnostic radiology.³⁰⁷ Ultrahigh field scanners have enabled the acquisition of highly resolved spectral data that permit more sophisticated signal quantifications, which include the correction of confounding effects such as direct water saturation (spillover), conventional broad MT, and interference with other metabolite resonances, for example, by using multipool Lorentzian fit analysis.^307–312 These approaches also allow quantification of multiple CEST pools simultaneously, for example, relayed nuclear Overhauser effects (rNOEs) and amine resonances.³⁰⁵ Generally, GRE-based acquisition provides a robust readout method for CEST at UHF. For spiral-centric reordered k-space acquisition, Zaiss et al³¹³ demonstrated with their Snapshot-CEST approach that the image quality can be further improved using a rectangular spiral reordering scheme adjusted to the field of view.

Neuroradiology

Studies of APT MRI assessing therapy response in patients with glioma found increased APT signals in tumors lesions with progressive disease compared with treatment-related changes or residual tumors classified as stable disease.^{307,314–317} In patients with newly diagnosed glioma, APT and rNOE CEST signals are associated with response to first-line therapy as reported in several studies.^{307,316,318,319} Amide proton transfer mediated CEST effects have been shown to be associated with World Health Organization tumor grade and cellularity^320–325 and to be correlated with the IDH mutation status in gliomas.^324,326 Highest sensitivity and specificity for IDH status prediction were achieved at 7 T using the downfield rNOE-suppressed APT metric.³²⁴ Relayed nuclear Overhauser effect imaging at 7 T has also been found to be associated with tumor grade^327,328 and cellularity.³²⁹ For 7 T APT imaging at initial diagnosis of patients with glioma, an inverse signal correlation with overall survival and progression-free survival has been found.^307,319

The majority of CEST studies at UHF have been applied in neuro-oncological diseases. At 3 T MRI, a broader spectrum of neurological diseases has already been investigated. Recently, a multipool CEST MRI approach has been demonstrated to be feasible at 7 T in patients with acute ischemic stroke.³³⁰ In addition, APT imaging at 7 T has been applied to study radionecrosis after stereotactic radiosurgery of AVM.³³¹

For the detection of Glu in the human brain, GluCEST MRI has been proposed by Davis et al.³³² GluCEST signals have been shown to enable correct lateralization in temporal lobe seizure.³³² Moreover, peritumoral GluCEST signals were associated with recent seizures and drug-refractory epilepsy in patients with glioma.³³³

Body Applications

Chemical exchange saturation transfer MRI has also been applied in other organs and diseases at UHF, whereas a much wider range of applications has been explored at 3 T field strength. Investigations in patients with breast cancer at 7 T showed a positive correlation between APT CEST signal intensity and tumor cellularity^334–336 and indicated that APT CEST may enable detection of early therapy response during neoadjuvant chemotherapy.³³⁷ Figure 8 shows 2 patients with biopsy-proven breast cancer. Increased APT signals at 7 T corresponded well with gadolinium contrast-enhancement in the tumor region.

FIGURE 8.

Relaxation-compensated APT CEST-MRI at 7 T and clinical MR mammography. Patient 1: high grade/patient 2: intermediate grade intraductal breast cancer of no special type. In both patients, a strong gadolinium enhancement can be observed at clinical MRI: gadolinium-enhanced (Gdce), fat-saturated T₁-weighted MRI after administration of a standard dose (0.1 mmol/kg body weight) of gadobutrol (TR, 28 milliseconds; TE, 4.76 milliseconds; slice thickness, 1.1 mm; flip angle, 25; field of view, 360; matrix, 320) and subtraction MRI. In addition, T₂-weighted TSE (1c, 2c) and the APT_AREX contrasts at 7 T are shown. All breast cancers could be clearly identified on the APT_AREX contrast. APT signal hyperintensities showed a distinct morphological correlation with the contrast-enhanced MR images. Reproduced with permission from Elsevier, Loi et al.³³⁵

For MSK applications, the detection of GAGs of articular cartilage at 7 T has been demonstrated.^338,339 A major advantage of gagCEST compared with other GAG-sensitive MRI techniques, such as sodium MRI and dGEMRIC, is the comparably short acquisition time for full 3D coverage of a knee joint in approximately 10 minutes.³³⁹

Exogenous Chemical Exchange Saturation Transfer Agents

The CEST contrast produced by a probe depends on multiple parameters including concentration, proton exchange rate, number of exchangeable protons, T₁, T₂, saturation scheme, and so on.³⁴⁰ The use of exogenous agents to generate contrast via chemical exchange generally faces the challenge of relatively low in vivo sensitivity. However, sensitivity can be improved by using agents that accumulate in the diseased tissue.³⁴¹

One biodegradable agent that has recently gained considerable attention is natural d-glucose for dynamic glucose-enhanced (DGE) MRI. The indirect detection of glucose via chemical exchange-sensitive MRI (ie, CEST or chemical exchange-sensitive spin-lock [CESL]) enables strong signal amplification. The detected signal is proportional to the local concentration change of glucose after intravenous administration.³⁴² Demonstrations of feasibility of DGE MRI in patients with glioma were performed by Xu et al³⁴³ using CEST and by Schuenke et al^344,345 and Paech et al³⁴⁶ using adiabatically prepared CESL MRI. Glucose contrast enhancement has been reported, especially in areas of disrupted blood-brain barrier (BBB), suggesting major signal contributions from BBB leakage and tissue perfusion.^343–347

However, increased glucose concentrations were also found in areas outside the disrupted BBB.^344,346 In contrast to gadolinium-based contrast agents, glucose is not confined to the intravascular space and the extracellular extravascular space. Furthermore, CEST and CESL signals may also be altered by local pH, because an acidic microenvironment may modulate the proton exchange rate.³⁴⁸

It must be noted that DGE MRI contrasts are prone to motion-induced artifacts and therefore require sophisticated motion correction approaches.^349,350 At 3 T field strength, small effect sizes currently limit robust signal quantification.^351,352 Dynamic glucose-enhanced MRI may therefore profit from the fact that the number of UHF scanners in clinical units is continuously increasing, possibly paving the way for wider clinical exploration.

BEYOND 7 T

In the future, further increases in field strength will advance our capabilities in clinical research and assuredly lead to significant advances in these MRI techniques, although they will initially not be applied for the clinical workup of individual patients. As mentioned in the introduction, there is already 1 human MRI system operating at 10.5 T and 3 systems operating at 11.7 T are in the process of installation. Scientifically, the rationale for going to even higher magnetic fields are clear,^353–355 and plans to implement MRI systems at 14 T are being pursued in several countries around the world, including China, Germany, the Netherlands, and the United States. In particular, the magnets of these systems represent a significant engineering challenge, because niobium-titanium, the superconductor almost exclusively used for human MRI magnets up to 11.7 T, is no longer a viable alternative at higher magnetic fields. A 14 T magnet will have to incorporate at least some niobium-tin or high-temperature superconducting materials with superior superconducting performance parameters.³⁵⁶ These materials are more expensive and more difficult to manufacture than niobium-titanium, so financing a 14 T MRI system will be an economic in addition to technical challenge; however, preliminary design studies indicate that, because of the higher material performance, less superconducting wire is needed overall than with a scaled-up niobium-titanium design, so the cost and magnet size do not scale as severely as expected.

Ultimately, the upper limit on magnetic field strength for human MRI will be set by physiologic, not technical considerations. Human studies up to 10.5 T have thus far failed to reveal any severe or permanent physiologic effects related to the magnetic field,³⁵⁷ that is, no significant cognitive effects or increases in blood pressure or heart rate. Animal studies in rats suspended in a vertical 14 T field showed that there were significant interactions with the vestibular system,³⁵⁸ leading to the animals circling in a preferred direction after exposure. However, the authors noted that the orientation of the human vestibular system to the main magnetic field in a classical solenoidal design with the magnetic field along the axis of the body is less conducive to inducing the observed effects, so that they postulated that 14 T exposure might not have similar consequences in humans.³⁵⁸ Further research on the physiologic underpinnings of vestibular interactions supports this supposition,³⁵⁹ as the main mechanism is now considered to be related to ionic currents in the endolymph of the inner ear interacting with the main magnetic field. The orientation of ionic flow relative to the magnetic field determines the severity of the effects, and the vector cross product is lower in humans than in rats or mice. Another area of physiologic interaction is magnetohydrodynamic effects that occur in the electrically conducting flowing blood. Experimentally unconfirmed theoretical calculations indicate that volume flow rate in the aorta might be reduced by roughly 10% at 15 T,³⁶⁰ leading to regulatory compensation in heart rate or blood pressure. Thus, although physiologic considerations are not expected to limit MRI application up to 14 T, these aspects will have to be critically examined with each elevation in field strength.

Systems beyond 7 T are all targeted toward fundamental research, either for studying brain function or for understanding healthy human physiology and aging or the pathophysiology of various diseases. Given the challenges involved, it is unlikely that any field strength beyond 7 T will be considered for diagnosis in individual patients for at least a couple of decades. However, knowledge gained with such systems about disease processes in groups of individuals and associated technological advancements may “trickle down” to lower field strength systems that are used clinically.

SUMMARY

Although UHF MRI has been the subject of intense research for over 2 decades, several significant challenges remain. Most pressing currently is the need for clinical approval of pTx technology including multichannel transmit RF coils that can expand the application domain outside the brain and small joints to the thorax, abdomen, pelvis, and specific organs such as the breasts. pTx technology will not only facilitate excellent image quality throughout the body, but could also facilitate the examination of patients with implants, who represent a continually increasing proportion of the patient population as implants become more widespread. Only very few implants have thus far been certified as MR-conditional for 7 T.¹²⁴ Beyond the obvious danger of magnetic forces and torques, RF interactions and heating around the implants is of concern, and pTx can help by modulating the electric RF field responsible for heating.^361,362 Finally, even if all the technical challenges can be satisfactorily resolved, the role of 7 T in the clinical workup of patients will be strongly influenced by economic considerations. A 7 T examination is definitely more expensive than an examination at 3 T or 1.5 T, but to secure higher reimbursement rates, 7 T must demonstrate enhanced clinical value, and this is still an ongoing process.

Despite these outstanding challenges, the introduction of UHF scanners has already had a major influence on the possibilities in clinical neuro and MSK MRI. Advanced clinical evidence of added diagnostic value has for instance been demonstrated in patients with epilepsy by the “7 T Epilepsy Task Force” through the collection of over 2000 data sets from twenty-one 7 T MRI centers.⁹² All MRI techniques, including SWI, MPRAGE, as well as TOF MRA, profit considerably from the boost in SNR and CNR, which permits high-resolution MRI. This enables the precise visualization of anatomical substructures or cerebral blood flow or cartilage disease, greatly benefiting clinical decision making. Furthermore, UHF proton MRI permits the identification of novel MR biomarkers that provide information about diseases such as brain cancer or epilepsy. In addition to this gain in morphological information, UHF MRI enhances the specificity of fMRI techniques. In fMRI, advances in field strength permit submillimeter detection of the BOLD signal, providing insights into brain connectivity. The advent of UHF scanners has sparked significant progress in preclinical techniques such as CEST MRI, DGE MRI, or X-nuclei MRI, techniques that furnish metabolic information about physiological and pathophysiological processes. In the near future, all these promising methods and encouraging results need to translate into clinical evidence, which requires dedicated, large-cohort prospective trials to prove patient benefit. Ultrahigh field MRI already plays a key role in neuroscience and preclinical research into disease pathology, and its role in clinical diagnostics is sure to expand as more systems with clinical approval as medical devices are installed and its added value in the clinic is established and validated.